tbuckley/cabot-search huggingface dataset:
Clinical and social importance of follow-up assessment of family members of patients with BRCA mutations.
Authors: Ivana Lucia de Oliveira Nascimento, Juliana Cortes Freitas, Thais Ferreira Bomfim-Palma, Juliana Lima Gomes Rodrigues, Thamara Ferreira Melo, Pollyanna Carozo Oliveira, Luciana Landeiro, Roberto Meyer, Maria Betania Toralles, Taisa Lopes
Journal: Journal of Clinical Oncology (2023)

10621 Background: The identification of BRCA1 and BRCA2 genes mutations are of paramount importance in the treatment and follow-up of hereditary cancer patients. When a pathogenic variant (PV) is identified in one of these genes, the surveillance for new primary tumors becomes individualized. When a pathogenic mutation is identified other family members may also be at high risk for developing tumors. Then the investigation should become familiar. Methods: This study reports the experience of a public oncogenetics service with the identification and follow-up of relatives of patients with BRCA mutations. Of the 1505 patients registered, 773 are probands, of which 71 had a mutation in one of the BRCA genes. A total of 503 family members were evaluated, with an average of 13 relatives per proband. Results: Of the 353 relatives with a BRCA1 mutation, 132 had the familial mutation, and only 18 had cancer diagnosis. The mean age of the evaluated family members was 37 years, lower than the mean age at diagnosis of the probands, which was approximately 41 years, two founder mutations in BRCA1 (NM_007300.4:c.3331_3334del and NM_007300.4:c.211A &gt; G) were more recurrent among index cases, which is associated with the ancestral background of the local population. For the BRCA2 gene, 148 family members were evaluated, of which 77 had a mutation and 23 had a previous cancer diagnosis. The mean age of family members evaluated for BRCA2 mutation was 43 years, similar to the mean age at diagnosis of the proband: 41 years. The NM_000059.4:c.1389_1390del and NM_000059.4:c.7124T &gt; G variants was the most frequent in BRCA2. Conclusions: This data reinforces the importance of genetic counseling and testing of family members when a pathogenic variant is identified in a cancer patient. It is clear that early initiation of surveillance protocols, with screening and prophylactic surgeries are very effective tools for those high risk patients, they just have to be early diagnosed with the PV to benefit from this strategies. In addition, this assessment helps in understanding the mutational profile of the population in order to improve the planning of services in oncogenetics.
Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements
Authors: M Nishi, M Eguchi-Ishimae, Z Wu, W Gao, H Iwabuki, S Kawakami, H Tauchi, T Inukai, K Sugita, Y Hamasaki, E Ishii, M Eguchi
Journal: Leukemia (2012)
Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management
Authors: Michelle A. Elliott, Ayalew Tefferi
Journal: American Journal of Hematology (2018)

Abstract Disease Overview and Diagnosis Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥ 25 x 10 9 /L of which ≥ 80% are neutrophils, with &lt; 10% circulating neutrophil precursors with blasts rarely observed. In addition, there is no dysplasia, nor clinical or molecular criteria for other myeloproliferative neoplasms. Update on Diagnosis Previously the diagnosis of CNL was often as one of exclusion based on no identifiable cause for physiologic neutrophilia in patients fulfilling the aforementioned criteria. The 2016 WHO classification now recognizes somatic activating mutations of CSF3R (most commonly CSF3RT618I ) as diagnostic, allowing for an accurate diagnosis for the majority of suspected cases through molecular testing. These mutations are primary driver mutations, accounting for the characteristic clinical phenotype and potential susceptibility to molecularly targeted therapy. Risk Stratification Concurrent mutations, common to myeloid neoplasms and their precursor states, most frequently in SETBP1 and ASXL1 , are frequent and appear to be of prognostic significance. Although data are evolving on the full genomic profile, the rarity of CNL has delayed complete understanding of its full molecular pathogenesis and individual patient prognosis.
Effects of Esophageal Pressure Monitoring on Sleep Architecture
Authors: RONALD D. CHERVIN, MICHAEL S. ALDRICH
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Esophageal pressure (Pes) monitoring can be performed during polysomnography with a thin, water-filled catheter connected to a transducer. The resulting quantitative assessment of respiratory effort aids in the diagnosis of sleep-related breathing disorders, but little is known about the potential effect of the procedure on sleep architecture. We monitored Pes during polysomnography in 155 patients and compared their sleep architecture with that of 155 matched patients who slept without esophageal catheters. Cases were matched for age, sex, and severity of respiratory disturbance during sleep. Esophageal manometry was associated with small but statistically significant (p < 0.05) decrements in total recording time, total sleep time, sleep efficiency, percent Stage 2 sleep, and percent rapid-eye-movement (REM) sleep, and with increases in latency to REM sleep, latency to persistent sleep, and percent Stage 3/4 sleep. The differences were of such small magnitude that their clinical significance is doubtful. The number of awakenings per hour of sleep, latency to sleep onset, and percent Stage 1 sleep were no different when esophageal manometry was used. We conclude that the effects of monitoring Pes on sleep architecture are minimal, and that the decision of whether or not to use the technique can be based to a large extent on whether quantitative information about respiratory effort will be useful.
Prognosis factors for long-term eribulin response in a cohort of patients with HER2-negative metastatic breast cancer.
Authors: Antoine El Kaddissi, Elsa Curtit, Laura Mansi, Christophe Borg, Guillaume Meynard
Journal: Journal of Clinical Oncology (2023)

e13120 Background: Eribulin is a drug used since 2010 in metastatic breast cancer. Some prognosis criteria for long progression-free survival are already described in small cohorts. We present an historic cohort to determine new prognosis criteria for long-term eribulin response in HER2-negative metastatic breast cancer. Methods: Our retrospective cohort include female patient with HER2-negative metastatic breast cancer treated with eribulin in Franche-Comté, France. We defined a long-term response as six months of eribulin treatment. The primary endpoint is the analysis of criteria that differ according to the progression-free survival. Secondaries outcomes concern overall survival, response rate and analysis of MDM2/p53 axis. Results: Median progression free survival (PFS) is 3.2 months. 23.6 percent of patients have a long-term response to eribulin. Four discriminant criteria appear to separate progression free survival in two arms (PFS &lt; 3 months or &gt; 6 months) predicting nearly 78% the probability of a prolonged response to eribulin: histological grade, presence of meningeal metastasis, response to prior chemotherapy and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival is 8.5 months. MDM2 amplification appear not being predictive of therapeutic response in metastatic breast cancer. Conclusions: Eribulin response in metastatic breast cancer can be drive by clinical and biological factors. The application of the nomogram proposed by our analysis can assist the clinician in the therapeutic strategy and prescription of eribulin. These results should be confirmed in real life. Multivariate logistic regression to predict PFS &lt; 3 months vs &gt; 6 months. [Table: see text]
RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across<i>FGFR2</i>Alterations and Resistance Mutations
Authors: Vivek Subbiah, Vaibhav Sahai, Dejan Maglic, Kamil Bruderek, B. Barry Touré, Songping Zhao, Roberto Valverde, Patrick J. O'Hearn, Demetri T. Moustakas, Heike Schönherr, Nastaran Gerami-Moayed, Alexander M. Taylor, Brandi M. Hudson, Damian J. Houde, Debjani Pal, Lindsey Foster, Hakan Gunaydin, Pelin Ayaz, Dina A. Sharon, Lipika Goyal, Alison M. Schram, Suneel Kamath, Cori Ann Sherwin, Oleg Schmidt-Kittler, Kai Yu Jen, Fabien Ricard, Beni B. Wolf, David E. Shaw, Donald A. Bergstrom, James Watters, Jessica B. Casaletto
Journal: Cancer Discovery (2023)

Abstract Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates &amp;gt;250- and &amp;gt;5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models—including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi—while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting. Significance: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1–4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949
Prognostic value of systemic inflammatory response in early-stage triple-negative breast cancer.
Authors: Tanja Ovcaricek, Erika Matos, Masa Auprih, Simona Borstnar
Journal: Journal of Clinical Oncology (2023)

e14562 Background: Among breast cancer (BC) triple-negative (TN) subtype is the most immunogenic. Host and systemic immune response characterised by tumor-infiltrating lymphocytes (TILs) and immune cells in peripheral blood shape the net anti-tumor immune status. The systemic immune-inflammation index (SII) represents an effective indicator of the peripheral immune status. To date, TILs and SII have been largely examined separately. Therefore, in the present study, we investigated the prognostic value and relationship between pretreatment TILs and SII in a large number of unselected patients (pts) with early (e) stage TNBC. Methods: A total of 301 consecutive eTNBC pts treated with curative intent at Oncology Institute Ljubljana from January 2000 till August 2007 were investigated. Histopathological and clinical data were obtained retrospectively from the medical records. TILs were scored as intensive vs others. SII was determined by platelet × neutrophil/lymphocyte. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The optimal cut-off value of SII was 675 and was evaluated using the receiver operating characteristic (ROC) curve. Results: The median follow-up period was 17,6 years (16.9-18.3), and the entire cohort`s 10-year DFS was 67.5% and 10-year OS 72.1%. The median age was 54 (53-57) years. Most pts were diagnosed node negative (40.7%), with larger tumors (≥ 2 cm, 57.1%), grade 3 (83.5%) and underwent perioperative chemotherapy (cht) (81%). Patients with positive lymph nodes (LN) had higher SII (r=0.21, p=0.003), no correlation between LN and TILs was found. Patients with higher TILs had significantly better OS (HR: 0.40, 95% CI 0.37-0.97, p=00.004), and lower SII predicted significantly better DFS and OS (HR for DFS: 1.65 95% CI 1,03-2.67, p=0.038, HR for OS: 1.72, 95% CI 1.11-2.65, p=0,015). In multivariate analysis, positive LN status retained its independent prognostic value for worse DFS and positive LN and higher SII for worse OS. Conclusions: Our data confirms important role of systemic immune response in the prognosis of eTNBC. The survival of these pts is significantly influenced by the pretreatment SII and TILs, the prognostic value of SII seems to be stronger in our cohort. However, positive lymph node status remains the strongest predictor for worse survival in eTNBC. [Table: see text]
Data transparency and demographic representation in approval packages of FDA-approved oncology drugs from 2012-2021.
Authors: Jingyi Liu, Gowri Jayaram, Tanvee Varma, Stephen Sammut, Carmen Guerra, Jennifer E. Miller
Journal: Journal of Clinical Oncology (2023)

1594 Background: Over the past decade, the U.S. Food and Drug Administration (FDA) has leveraged regulations and guidance documents to accelerate improvements in demographic reporting and encourage adequate representation of minorities in clinical trials. This cross-sectional study aims to assess the impact of these interventions by characterizing demographic data reporting and representation by sex, age, and racial and ethnic identity in pivotal trials supporting novel cancer therapeutics approved by the FDA from 2012 through 2021. Methods: Study demographic data were abstracted from FDA drug approval packages and US cancer population demographic data was abstracted from US Cancer Statistics. The percentages of trials reporting sex, age, racial and ethnic identity of participants in drug approval packages were calculated and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of participants in each demographic by the percentage of the US cancer population in each group. PPRs were constructed for each pivotal trial by cancer type. Adequate representation was defined as PPR 0.8-1.2 and the proportion of trials which were adequately representative of each demographic was calculated and trended over time. Results: From 2012 through 2021, the FDA approved 118 cancer therapeutics, based on 131 pivotal trials. For drugs approved 2012-2016, the majority of associated pivotal trials reported participation based on sex (100% of trials), age (100%) and White (98%), Black (75%) or Asian (84%) racial identity, but not American Indian or Alaskan Native racial identity (18%) or Hispanic ethnic identity (41%). For drugs approved 2017-2021, there were no significant improvements in demographic data reporting, although there was a trend towards increased reporting on Hispanic ethnic identity from 2012-2016 (41%) to 2017-2021 (65%) (p= 0.06). For drugs approved 2012-2016, most pivotal trials adequately represented female participants (78% of trials) and participants identifying as White (87%), but few pivotal trials adequately represented older adults (7%), participants identifying as Black (11%), American Indian or Alaskan Native (0%), Asian (18%) or Hispanic (5%). Representation in pivotal trials did not significantly improve for any demographic for drugs approved 2017-2021 (p&gt;0.05). Conclusions: This study found that the last decade’s efforts to improve demographic data transparency and representation in clinical trials have not yet borne fruit for novel cancer therapeutics. More consequential FDA regulations may be necessary. Beyond the FDA, demographic data transparency and adequate minority representation in oncology clinical trials is an all-stakeholder responsibility. A more just clinical trial infrastructure requires greater collaboration between the FDA, sponsors, enrollers, contract research organizations and cooperative groups.
Biomaterial‐based gene therapy
Authors: Yi Yu, Yijun Gao, Liming He, Bairong Fang, Wenhui Ge, Pu Yang, Yikun Ju, Xiaoyan Xie, Lanjie Lei
Journal: MedComm (2023)

Gene therapy, a medical approach that involves the correction or replacement of defective and abnormal genes, plays an essential role in the treatment of complex and refractory diseases, such as hereditary diseases, cancer, and rheumatic immune diseases. Nucleic acids alone do not easily enter the target cells due to their easy degradation in vivo and the structure of the target cell membranes. The introduction of genes into biological cells is often dependent on gene delivery vectors, such as adenoviral vectors, which are commonly used in gene therapy. However, traditional viral vectors have strong immunogenicity while also presenting a potential infection risk. Recently, biomaterials have attracted attention for use as efficient gene delivery vehicles, because they can avoid the drawbacks associated with viral vectors. Biomaterials can improve the biological stability of nucleic acids and the efficiency of intracellular gene delivery. This review is focused on biomaterial-based delivery systems in gene therapy and disease treatment. Herein, we review the recent developments and modalities of gene therapy. Additionally, we discuss nucleic acid delivery strategies, with a focus on biomaterial-based gene delivery systems. Furthermore, the current applications of biomaterial-based gene therapy are summarized.
Gut bacterial metabolism contributes to host global purine homeostasis
Authors: Kazuyuki Kasahara, Robert L. Kerby, Qijun Zhang, Meenakshi Pradhan, Margarete Mehrabian, Aldons J. Lusis, Göran Bergström, Fredrik Bäckhed, Federico E. Rey
Journal: Cell Host & Microbe (2023)

The microbes and microbial pathways that influence host inflammatory disease progression remain largely undefined. Here, we show that variation in atherosclerosis burden is partially driven by gut microbiota and is associated with circulating levels of uric acid (UA) in mice and humans. We identify gut bacterial taxa spanning multiple phyla, including Bacillota, Fusobacteriota, and Pseudomonadota, that use multiple purines, including UA as carbon and energy sources anaerobically. We identify a gene cluster that encodes key steps of anaerobic purine degradation and that is widely distributed among gut-dwelling bacteria. Furthermore, we show that colonization of gnotobiotic mice with purine-degrading bacteria modulates levels of UA and other purines in the gut and systemically. Thus, gut microbes are important drivers of host global purine homeostasis and serum UA levels, and gut bacterial catabolism of purines may represent a mechanism by which gut bacteria influence health.
A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal
Authors: B. Bardoni, E. Zanaria, S. Guioli, G. Floridia, K. C. Worley, G. Tonini, E. Ferrante, G. Chiumello, E. R. B. McCabe, M. Fraccaro, O. Zuffardi, G. Camerino
Journal: Nature Genetics (1994)
Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group
Authors: D Tomizawa, K Koh, T Sato, N Kinukawa, A Morimoto, K Isoyama, Y Kosaka, T Oda, M Oda, Y Hayashi, M Eguchi, K Horibe, T Nakahata, S Mizutani, E Ishii
Journal: Leukemia (2007)
68Ga-DOTATOC PET/CT in Pancreatic Metastasis From Clear Cell Renal Cell Carcinoma
Authors: Nabeel Mansour, Kasturi Rangan, Reinhold Tiling, Johannes Rübenthaler, Matthias P. Fabritius
Journal: Clinical Nuclear Medicine (2023)

We present a rare case of a 74-year-old woman who underwent 68 Ga-DOTATOC PET/CT imaging for a suspected neuroendocrine tumor (NET) in the pancreatic head. PET/CT showed a solitary high somatostatis receptor (SSTR)-expressing lesion in the pancreatic head. Fine-needle aspiration of this lesion revealed a metastasis from a clear cell renal cell carcinoma (ccRCC). The patient had undergone nephrectomy 16 years prior due to ccRCC of the right kidney. Our case demonstrates that metastases originating from RCC can have high SSTR expression and therefore might mimic well-differentiated neuroendocrine tumors in 68 Ga-DOTATOC PET/CT.
Unusual Case of Missed Penile Metastases on 68Ga-PSMA PET/CT
Authors: Sydney A. Caputo, Graham Blair, Madeline Hawkins, Kendra Harris, Oliver Sartor
Journal: Clinical Nuclear Medicine (2023)

Abstract A 75-year-old man with a history of previously treated localized prostate cancer and prostate-specific antigen of 4.86 ng/mL was referred for a 68 Ga–prostate-specific membrane antigen PET/CT. PET imaging was reported to be negative. After subsequent review and re-read of the scan, prostate-specific membrane antigen imaging revealed uptake along the penile shaft (SUV max of 14.7). MRI was compatible with tumor. Penile metastases from prostate cancer, although uncommon, do occur and readers are encouraged to distinguish penile metastatic uptake from residual urine in the urethra.
Rapid Tumor Washout of 177Lu-PSMA Radioligand in Renal Cell Carcinoma
Authors: Jingjing Zhang, Christiane Schuchardt, Xiaoyuan Chen, Richard P. Baum
Journal: Clinical Nuclear Medicine (2023)

Abstract The role of prostate-specific membrane antigen (PSMA) targeted molecular imaging and radionuclide therapy in prostate cancer is well known. PSMA is also overexpressed in the neovasculature of a number of solid tumors, including renal cell carcinoma (RCC). Several studies have demonstrated the diagnostic utility of PSMA PET imaging in the setting of RCC. To date, no PSMA radioligand therapy of RCC patient has been reported according to literature. Here, we report our experience treating a patient with metastatic RCC with 177 Lu-PSMA I&amp;T radioligand therapy, but unexpected imaging findings with rapid washout of 177 Lu-PSMA from the tumor.
A Case of Pancreatic Cancer With Rare Cutaneous and Muscle Metastases on 18F-FDG PET/CT Imaging
Authors: Zeyu Zhang, Shiwei Guo, Changjing Zuo, Chao Cheng
Journal: Clinical Nuclear Medicine (2023)

Abstract A 46-year-old man underwent PET/CT for metastatic survey 6 years after radical resection of pancreatic cancer. In addition to the increased uptake observed in the operative area, increased FDG uptake was also observed in the left external abdominal oblique muscle and the left frontal scalp. Both intramuscular and subcutaneous lesions were surgically excised and diagnosed as metastases from pancreatic cancer.